CN102753169A - Topical transdermal dexmedetomidine compositions and methods of use thereof - Google Patents
Topical transdermal dexmedetomidine compositions and methods of use thereof Download PDFInfo
- Publication number
- CN102753169A CN102753169A CN2011800088869A CN201180008886A CN102753169A CN 102753169 A CN102753169 A CN 102753169A CN 2011800088869 A CN2011800088869 A CN 2011800088869A CN 201180008886 A CN201180008886 A CN 201180008886A CN 102753169 A CN102753169 A CN 102753169A
- Authority
- CN
- China
- Prior art keywords
- mpu
- pharmacy
- skin
- acceptable salt
- pain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Analgesic topical formulations of dexmedetomidine and methods of use thereof in the treatment and management of pain and other conditions.
Description
The reference of related application
The application requires the priority of the U.S. Provisional Patent Application 61/293,440 of submission on January 8th, 2010, and its full content is incorporated herein as a reference.
Inapplicable.
Background technology
Right MPU-295 (dexmedetomidine), 5-[(1S)-1-(2, the 3-3,5-dimethylphenyl) ethyl]-the 1H-imidazoles, be a kind of non-narcotic α calm and analgesia character that has
2-adrenoceptor agonists.
Right MPU-295
At present, the right MPU-295 of commercial application only is useful on the ejection preparation of calm effect, and only can carry out intravenous administration by the health care personnel of specialty.Although right MPU-295 has analgesic properties, yet do not obtain as yet commercial as the preparation of analgesics.And owing to a series of reason, the ejection preparation of commercial acquisition also is not suitable for the analgesics of autonomous administration.Therefore, have the unsatisfied demand that continues for the analgesic based on right MPU-295, this analgesic for example can independently be administered for and produce analgesic activity (or treating in other cases or prevent irritation), and does not have sedation.
Summary of the invention
The application has described the analgesia preparation capable of permeating skin of right MPU-295, the acceptable salt of its pharmacy and its derivant, and method of use thereof.
The application provides the analgesia preparation capable of permeating skin of novel right MPU-295, the acceptable salt of its pharmacy and/or its derivant, and they are used to treat or the application process of prevent irritation.This pharmaceutical composition comprises: the right MPU-295 or acceptable salt of its pharmacy or the derivant (for example prodrug) that are enough to produce the amount of analgesic activity (for example, treatment or prevent irritation); And the acceptable transdermal delivery carrier of pharmacy; And other optional member, such as, but be not limited to viscosity modifier, pH regulator agent, antiseptic, excipient, emulsifying agent, buffer agent, coloring agent etc.Right MPU-295 in the acceptable transdermal carrier of pharmacy (vehicle) or the acceptable salt of its pharmacy or derivant (for example prodrug) can be packaged in proper container or the device.
In an exemplary embodiment; A kind of method that gives right MPU-295 or acceptable salt of its pharmacy or derivant to mammal comprises: the transdermal composition of predetermined close is applied (apply) on mammalian skin; Said composition is included in right MPU-295 or acceptable salt of its pharmacy or the derivant in the acceptable transdermal delivery carrier of pharmacy; The Transdermal absorption that the amount of compositions can effectively provide the right MPU-295 of pharmacy effective dose to get into mammal systemic circulation system (systemic circulatory system, systemic circulatory system) through mammal skin.When dosage was suitable, through Transdermal absorption, right MPU-295 played analgesic activity (analgesia) in mammal, and does not have sedation (sedation).
Through with reference to the following specific embodiment and embodiment, can understand more characteristic.
Description of drawings
Fig. 1 through chart show to the people use its exemplary formulation be administered once every day after the PC-time graph with respect to prediction of observation under the stable state.
Fig. 2 through chart show to the people use its exemplary formulation be administered twice every day after the PC-time graph with respect to prediction of observation under the stable state.
Fig. 3 shows through chart and uses its exemplary formulation to people's predicting the outcome after administration in many days that be administered once every day.
Fig. 4 shows through chart and uses its exemplary formulation to people's predicting the outcome after administration in many days that be administered twice every day.
Fig. 5 shows through chart and uses preparation (Formula) 1-85 in the intravital administration result of Canis familiaris L..
Fig. 6 shows through chart and uses preparation (Formula) 1-53 in the intravital administration result of Canis familiaris L..
Fig. 7 shows through chart and uses preparation (Formula) 1-83 in the intravital administration result of Canis familiaris L..
The specific embodiment
This paper provides the novel right MPU-295 or the analgesia preparation capable of permeating skin of acceptable salt of its pharmacy or derivant, and they are used for the method for treatment and processing (management) pain.
Right MPU-295 is a species specific α
2-adrenoceptor agonists has calmness, anesthesia and analgesic activity to mammal.For the mankind, right MPU-295 carries out calmness in the commercial process that is used under the Critical Care environment treatment to the patient of initial infusion therapy and mechanicalness oxygen supply, and to before operation and other programs or the not intubated patient in the process carry out calmness.With reference to United States Patent (USP) 6,716, No. 687 and 6,313, No. 311.
The human pharmacokinetics characteristic of right MPU-295 behind intravenous injection (i.v.), intramuscular injection (i.m.) and transdermal administration all there is research.The average elimination half-life after intravenous injection and the intramuscular injection is respectively 1.5h and 3h, and the elimination half-life behind the transdermal administration is 5.6h.Behind intramuscular injection and the transdermal administration, the time that reaches Cmax in the blood is respectively 1.6-1.7h and 6h, and it is 73% and 88% that absolute bioavailability is estimated respectively.Referring to for example " pharmacodynamics and pharmacokinetic after the right MPU-295 intramuscular injection ", Scheinin etc., clinical pharmacology treated for 52 phases, 53-46 (1992); " pharmacokinetics and the hematodinamics effect of the right MPU-295 of vein and intramuscular injection hydrochloric acid in the adult volunteer ", Dyck etc., 78 phases of anesthesiology, 813-20 (1993); And " pharmacokinetics of right MPU-295 preparation capable of permeating skin and pharmacodynamic study ";
etc.; Europe clinical pharmacology 46 phases of magazine, 345-49 (1994).
Right MPU-295 is known also can be from its hetero-organization, as absorbing in the oral cavity.After the buccal gave, wherein people experimenter was contained right MPU-295 solution but is not swallowed in mouth, and average buccal bioavailability is measured as 81.8%, and peak concentration time is about 1.5h, and apparent elimination half-life is 1.9h.Reference example as, " health volunteer's blood vessel gives the bioavailability of right MPU-295 outward ", Anttila etc., 56 phases of Britain's clinical pharmacology magazine, 691-93 (2003).
According to the present invention, but right MPU-295 administration of human or animal subjects are used for alleviation, processing, elimination, prevent irritation, or treat pain in other cases.In one exemplary embodiment; The method that mammal is given right MPU-295 or acceptable salt of its pharmacy or derivant comprises: the right MPU-295 or the transdermal composition of acceptable salt of its pharmacy or derivant that are included in the pharmaceutical acceptable carrier of predetermined close are applied (coating) to mammalian skin, the absorption that the amount of said composition can effectively provide the right MPU-295 of medicine effective dose to get into systemic circulation system through mammalian skin.After percutaneous absorbed, right MPU-295 was brought into play analgesic activity in mammalian body.
For example, although carry out chronic analgesia therapy, many patients that suffer from tumor or other disease continue to stand moderate to severe pain, and frequent increase owing to patient's level of activation, and intermittent sudden pain (breakthrough pain) occurs.The appearance that trial is offset this pain through the consumption that increases the long-acting analgesic preparation, but its onset is slow and have calmness, constipation, nauseating, vomiting side effect, and the side effect of opioid analgesic is especially obvious.Yet; The right MPU-295 preparation capable of permeating skin that has analgesic activity described in the literary composition provides a kind of analgesic activity of potential non-narcotic; Preferably delay, long-acting, controlled analgesic activity, their combinations are used for alleviation, control, treatment, prevent irritation or treatment pain.Treatment can comprise the right MPU-295 preparation capable of permeating skin of independent application, or with other right MPU-295 preparation Combined application (like Sublingual, through mucous membrane, injection), and/or with other analgesia component (like NSAIDS, anesthetis etc.) Combined application.
Right MPU-295 product described in the invention is the transdermal medicine preparation that is used for treating pain.Used term " pharmacy is acceptable " comprises in the scope that drops on reliable medical judgment and is applicable to human and animal's tissue and contacts in the literary composition; Do not have over-drastic toxicity, zest, anaphylaxis or other problem or complication, and have a rational benefit/risk ratio simultaneously and produce those chemical compounds, material, compositions, dosage form, packing and the method for using thereof of required pharmacological reaction.
Right MPU-295 comprises basic nitrogen atom, can form the acceptable salt of pharmacy with the acceptable acid of pharmacy.Term " the acceptable salt of pharmacy " refers to the organic and inorganic acid addition salt of nontoxic relatively right MPU-295 in this respect.These salt can finally separate and the right MPU-295 process of purification made acid-stable in situ, or through preparing to separate the salt that obtains after the sour reaction separately of right MPU-295 of the purification of its free alkali form and the organic or inorganic that is fit to.And salt possibly form in the process of preparation preparation capable of permeating skin.The typical acceptable salt of pharmacy comprises halogen acid salt (hydrohalide) (comprising hydrobromate (hydrobromide) and hydrochlorate (hydrochloride)), sulfate, disulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laruate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinate, tartrate, how hydrochlorate, mesylate, gluceptate, Lactobionate, 2-isethionate, dodecane sulfonate etc.Reference example is like " pharmacy salt ", Berge etc., 66 phases of medical science magazine, 1-19 (1977).The right MPU-295 of hydrochloric acid is an instance of the acceptable salt of its pharmacy.In the preparation capable of permeating skin, use the right MPU-295 of hydrochloric acid to be superior to using right MPU-295 itself described in the literary composition, this is that the stability of the Oxidation of oxygen is better in the dissolubility of its hydrochlorate and the anti-environment because in some cases.
The derivant of right MPU-295 can comprise the covalent modification that forms prodrug.After the administration, prodrug derivant generates right MPU-295 through chemical modification in mammalian body.Prodrug can be used to advantageously change bio distribution, the pharmacokinetics of right MPU-295, or reaches the characteristic that other needs.For example, the reactive nitrogen available functional groups (functional groups) in the right MPU-295 is carried out derivatization, and this functional group can be by the cracking through enzyme, non-enzyme, reduction, oxidation, hydrolysis, to manifest active pharmaceutical ingredient.The application of this type prodrug is known (referring to for example R.B.Silverman, 1992, " drug design and pharmaceutically active organic chemistry ", U.S. academic press, the 8th chapter).For example, prodrug can separate and purifying compounds process in-situ preparing final, or through making with the purifying compounds of its free alkali form and the suitable independent prepared in reaction of derivatization reagent.
Right MPU-295 transdermal composition comprises one or more pharmaceutically acceptable carriers, for example is gel, ointment or the liquid of 30%-99.995% by weight.Carrier possibly be solvent, cosolvent or the non-solvent of right MPU-295 or acceptable salt of its pharmacy or derivant.The material that is fit to is a liquid, or has flowability under the room temperature, and at room temperature can keep its state component (compositions, compositions), under preferred ambient pressure and the high pressure.But applicable liquid is not limited especially with flowable component, and condition is its not required medicinal application of interfere compositions, and its treatment has right MPU-295 or the acceptable salt of its pharmacy or the derivant (the right MPU-295 of example hydrochloric acid) of consumption.The acceptable liquid of pharmacy comprises water, ethanol, dimethyl sulfoxine, propylene glycol, Polyethylene Glycol, propylene carbonate, the acceptable oil of pharmacy (like soybean oil, Oleum Helianthi, Semen arachidis hypogaeae wet goods) etc.But the acceptable flowable component of pharmacy comprises like emulsifiable paste, gel, suspending agent, lotion, serosity, ointment etc.But the acceptable liquid of pharmacy or flowable component are selected in order to lytic activity pharmacy composition, produce that it is stable, the suspending agent of homogeneous, or form any combination, mixture or the compatible compositions of other pharmacy of suspending agent and solution.
Except above-mentioned constituent, right MPU-295 preparation capable of permeating skin can comprise that one or more are not the excipient (excipient) of pharmaceutically active medicine, and these excipient can add in the preparation process, or are contained in the last pharmaceutical formulation.The instance of excipient for example comprises that the viscosity adjustment material is (like polymer, sugar, sugar alcohol, natural gum, clay, silicon dioxide (like polyvinylpyrrolidone (PVP)) (being about 0.01% to 65%) such as (silicas) by weight.Other excipient instance comprises antiseptic (like ethanol, benzyl alcohol, propyl p-hydroxybenzoate and methyl parahydroxybenzoate) (being about 0.001% to 20% by weight).Other excipient instance comprises buffer agent, pH regulator agent (like sodium hydroxide, citrate and citric acid) (being about 0.01% to 5% by weight).The instance of other suitable excipient especially also comprises coloring agent (being about 0.001% to 5% by weight), aromatic (being about 0.001% to 1% by weight), chelating agen (like EDTA) (being about 0.001% to 1% by weight), UV absorbent (being about 0.001% to 10% by weight) etc.The details of suitable preparation capable of permeating skin will be described in further detail in the following embodiment that further illustrates.
In addition, according to instruction of the present invention, prepare and the method for using this preparation is conspicuous to those skilled in the art.For example, right MPU-295 preparation capable of permeating skin can be put into practice to mix according to the commodity production of standard approval and prepare through composition described in the appropriate amount literary composition.With these excipient be added in the preparation with the acceptance (compliance) that improves patient or experimenter although, the purpose that improves bioavailability, extend the expiration date, reduce production and packing cost, comply with the requirement of mechanism and reach other.The relative quantity of every kind of composition should not exert an influence to the required pharmacological property and the pharmacokinetic properties of target formulation.
Right MPU-295 preparation capable of permeating skin with analgesic activity described herein is intended to directly in mammalian skin and/or mucosa (like oral cavity, nasal cavity, rectum or genitals mucosa) administration.Medicine is sent to be actually through transdermal route and is taken place---and the back gastrointestinal absorption is different with swallowing.Term " transdermal " is meant and passes or send through skin membrane (skin membrane).Term " pass through mucosa " is meant and passes or pass through mucosa delivery.Especially, " oral mucosa " delivering drugs comprises and passes sending of any tissue, particularly Sublingual in oral cavity, pharynx, larynx, trachea or the upper digestive tract, cheek, gingiva and maxillary mucosal tissue.
Transdermal administration allows medicine to get into the systemic blood circulation, therefore provides the direct whole body that is independent of gastrointestinal effects to give and avoids undesirable first (first-pass) hepatic metabolism of crossing.Compare with other route of administration, the Transdermal absorption of preparation right-of-center in political views MPU-295 of the present invention can have significantly more controlled and the duration that prolongs, and bioavailability is desirable, or even in administration after many days.And, owing to avoided first pass metabolism, can reduce the total amount of the active drug composition in the preparation, thereby reduce the risk (for example hypotension, calmness) that harmful side effect takes place, and bring the cost benefit to maker.
Preparation capable of permeating skin can give mammal, comprises that people, people's companion animals (like cat, Canis familiaris L.), domestic animal and other need its animal.Should understand, give regular dosage form, like tablet, capsule, syrup etc., or the injection analgesia preparation usually has problems to the non-human animal, and the preparation capable of permeating skin described in the literary composition is particularly useful for these animals of treatment.For child and old man, the use of transdermal delivery is compared other delivering methods and is also had identical advantage.
" analgesia " is meant and alleviates or the sensation of eliminate pain.Used as indicated, " pain " comprises clinical manifestation widely, and it has wide significance.Perception to pain is highly subjective, and mode and degree that different people experiences pain all have very big difference.IASP is defined as pain " a kind of and acute or potential tissue injury offending sensation relevant or that describe with this degree of impairment and the experience on the emotion ".In brief, pain comprises any sensation experience that causes sufferings, and is relevant with the offending sensation of its health.The non-limiting type and the inducement of pain comprise: and neuralgia, myalgia, hyperpathia (hyperalgesia), hyperpathia (hyperathia, hyperpathia), neuritis and neuropathy.Pain is normally potential physically different, like cancer or arthritic symptom.The pain of some type like migraine, does not have clear and definite reason.Pain also possibly caused like burn or surgical operation by physical trauma.Viral infection like varicella zoster virus (chickenpox and herpes zoster), also can bring pain.Giving up of chemicals such as ethanol or Drug abuse is also normal relevant with pain symptom.Therefore, the lexical or textual analysis of " pain " here is very extensive, and its application should not be limited under any special disease or disease.
" calmness " that this paper uses is meant that consciousness reduces, patient or the experimenter ability of keeping open airway and rule breathing pattern that has independently, continue wherein, and physical stimulation and spoken command made suitably and the ability that rationally responds." no sedation " is meant that the calm scoring of Ramsay (Ramsay Sedation Scale) classification of patient is not more than 3 grades here, and in other words, the patient belongs to one of following classification: 1 grade=anxiety, excitement or uneasy; 2 grades=cooperation, directed (sense of direction is arranged, oriented) and quiet; Or 3 grades=calm but instruction is responded.Here " significantly calm " refer to patient or experimenter the calm scoring of Ramsay classification more than or equal to 4 grades.Wherein 4 grades=sleep soundly; But it is sharp to glabella tapping or loud auditory stimulus reaction; 5 grades=sleep soundly; To glabella tapping or loud auditory stimulus delay of response; 6 grades=sleep soundly; Reactionless to pain stimulus." significantly calm " also tests oneself consistently with the patient through Stamford Sleepiness Scale (Stanford Sleepiness Scale) here, and the calm ranking that is tried the patient is more than or equal to 3 grades, wherein: 1 grade=sensation is active, dynamic, vigilance or regain consciousness; 2 grades=high-caliber functional, but not at peak value; Can concentrate one's energy; 3 grades=wake up, but lax; Respond but incomplete clearmindedness; 4 grades=some is dimmed, loosens; 5 grades=dimmed; Have no interest and keep clear-headed; Slow in action; 6 grades=tired, feel dizzy, do one's utmost to keep clear-headed; Want to lie down; Or 7 grades, no longer keep clear-headed, very sleep is gone in F.F.; The consciousness that similar daydream is arranged.
Right MPU-295 preparation described herein can give with other pain therapy medicine altogether, comprising: NSAIDS such as aspirin, ibuprofen, naproxen, celecoxib, acetaminophen and other cox-2 inhibitors; Opium class medicine such as codeine, oxycodone, morphine, methadone and fentanyl; Anticonvulsant and antiarrhythmics such as phenytoin and carbamazepine; Antidepressants such as amitriptyline, imipramine and venlafaxine.Thisly carry out the two administration simultaneously of its right-of-center in political views's MPU-295 and another kind of pain therapy medicine altogether simultaneously.Replacedly, because the long-acting characteristic of transdermal composition described herein, the patient can regularly give fugitive or long-acting pain medication, and the right MPU-295 of transdermal can give or give sometimes as required on the same day as required.In some case, because right MPU-295 produces useful synergism, initial (primary) Drug therapy is had additional, therefore the dosage of interchangeable pain therapy medicine can reduce.Right MPU-295 especially can significantly strengthen the curative effect of Opium class, therefore under the situation that keeps identical curative effect, can reduce the dosage of required Opium class.
Have the right MPU-295 of analgesic activity or the preparation capable of permeating skin of acceptable salt of its pharmacy or derivant and preferably be provided in the dosing, so that the active pharmaceutical ingredient of scheduled volume suitably gives to the experimenter with medicine effective quantity.For example, preparation capable of permeating skin can be provided in single dose package or a plurality of packing unit, and as a bulk container (containers, bulk container), it comprises multiple dose in a system, and this system comprises the sealed container of being furnished with dosing pump.Representative is that the patient can the external self-administer be treated through activating from this pump one or many.The actuating of each pump can obtain the dosage of a metering.This advantage of sending be can single is discrete apply in the ability through single dose titration patient as required.And the medicine of other type is sent (like patch, lozenge, tablet and suppository) and is not had this kind sometimes, wherein, gives list-size-be suitable for-all dosage (one-size-fits-all dosage) with standard scheme.Another advantage of topical transdermal preparation comprise its use simple, particularly under not having the situation of health care professional during automedication.
The characteristics of pumping function allotter (pump action dispenser) are need apply ambient pressure to be used for driving, for example, outside manually, machinery or electricity cause pressure.This is opposite with compression system, and for example, the aerosol of propellant actuated or Compressed Gas are sprayed, and discharge through controlled pressure and typically realize driving, like opening through control valve.In specific implementations, the pump preparation preferably uses the pump spraying with preparation described herein, and it allows the administration of known quantity, can control the preparation size simultaneously.In other embodiments, the pressure system that comprises compressed propellant gas (for example, carbon dioxide, nitrogen, fluorochlorohydrocarbon class, Fluohydric acid. (hydrofluoroalkane) etc.) reservoir can produce the suitable dispensing amount.In certain preferred embodiment, the viscosity of delivery formulation has further increased surface area, and it is through being uniformly coated on skin or the mucosa, rather than at skin and mucosa with than thick-layer friction (comparing with emulsifiable paste) like gel.Density (emulsifiable paste and foam and gel phase contrast) helps the thickness of compositions on ideal pattern and skin or the mucosa.
The atomizing pump device can measure in advance, or replacedly, this device can be (device-metered) of device metering.Metering device preferably contains the dosage or the part of the dosage in some cell type (the for example single dosage unit solution of previous measurement in advance; Single or a plurality of bubble chambers (blister) or other chamber (cavity)), these parts are in the preparation process or before the patient uses in the introducing device.The typical devices metering units has reservoir, and it holds the preparation that enough is used for multiple dose, when the patient activates, can send with the spraying of metering through installing self.The amount of the medicine that device can be sent (like the dosage of each actuating) and each dosing interval duration measure.Limit each delivery time and can prevent excessive use to the frequency of patient's dosage delivered through restriction.
Make repeatability and any distribution mechanism or transdermal delivery carrier that Consideration comprises preparation.Keep the repeatability of these parameters in the keeping life process; And be very important at functional (like spray system, electrical nature, the pick off etc.) of in its whole service life, guaranteeing device under patient's service condition; Because any change may cause the variation of dosage and absorption in these parameters, this possibly cause potential side effect and curative effect to lower.
Any device is to design, repeatability and the performance characteristics that dosage possibly depend on container closure system (container closure system) that give of preparation.For the right MPU-295 product with correct performance, the appropriate device that required distribution is provided is an important factor.Driving parameters (like power, speed, maintenance and time of return) also is the factor that device need be considered.And device should be compatible with formulation components.Further, when the patient used to specifications, device should be designed to prevent part metering or the overdose to right MPU-295 preparation that its right-of-center in political views's MPU-295 preparation comprises right MPU-295 and acceptable salt of pharmacy or derivant.
A typical formulation device comprises elementary cell, release actuator, is used for the hole of preparation from device release, and reservoir.Before distributing the patient, reservoir preferably is filled with medicine and other excipient (like liquid-carrier, excipient etc., other part narration in the text), for example, and in manufacturing site location (site).The right MPU-295 of the amount of releasable measurement or acceptable salt of its pharmacy or derivant after actuating of reservoir preferred definition.Reservoir body can be any acceptable material, for example, simply formed by plastics, steel such as rustless steel, the transparent material etc. of a pitch circle cylindrical hollow, so it is very easy to preparation.Actuator is movably with respect to the hole that is used to activate release, can be provided in and provides this device (being provided at by the device) on the device.In activating the process that moves, reservoir is opened, and for example, through puncture (puncture), from the hole, provides single-dose dosage.Actuating after original position is advanced in the part process, has set up boost (environment).In actuating movable part subsequently, with identical direction, medium removes in the pressure solutions of one of both sides, and is conveyed to the place, hole.In this way, under pressure, medium is released from reservoir, and passes through the hole.
Usually, when any sprayable preparation capable of permeating skin left the hole, the track that drop is followed received hole shape and the influence of exerting pressure.In some embodiments, drop size, spray geometry and spray pattern depend on the design and/or the preparation nature of pump.In certain embodiments, the design of positional actuator, pump and preparation nature can be to spraying symmetry and form generation influences.Spray pattern also can be optimised, and so that drop is disperseed with path widely, so the surface area that chemical compound is absorbed on the skin increases.Any this sprayer unit can be further designed to, and makes things convenient for patient's application, and makes things convenient for the layout of spraying of skin special area.
Embodiment
Following right MPU-295 preparation capable of permeating skin prepares as embodiment.The certain exemplary preparation is tested on mammal, and is described in the text.
Embodiment 1a-placebo (placebo) transdermal gel preparation (carrier)
Be used for preparing the exemplary composition and the method for 50g methyl salicylate/aqua methnae alcohol clear gel (Methyl Salicylate/Menthol Hydroalcoholic Clear Gel).
Table A: 50g methyl salicylate/aqua methnae alcohol clear gel (RECRO1-45)
The method for preparing of table B:50g methyl salicylate/aqua methnae alcohol clear gel (RECRO1-45)
In this embodiment, inventor's note is following: 1) pH=0.592g, and produce a large amount of white agglomerates (white precipitate, white mass) after adding water; With 2) add entry rehydration or redissolve gel and also produce deposition.The deposition effect is considered to result from more water and adds the soluble of back methyl salicylate.In addition, part is relevant with pH value at least in sedimentary generation.
The right MPU-295 gel preparation of embodiment 1b-transdermal
Table C: the 50g gel preparation (RECRO1-53) of [0.5mg/g Dex HCl] concentration
| Component No. | Material | g/50g |
| 1 | Methyl salicylate/aqua methnae alcohol clear gel (lot number Recro 1-45) | 49.975 |
| 2 | The right MPU-295 of hydrochloric acid | 0.025g |
Table D: the method for preparing of the 50g gel preparation (RECRO1-53) of [0.5mg/g Dex HCl] concentration
| Step | Explanation |
| A | Distribute component No.1 in the 100ml glass beaker |
| B | Add component No.2 |
| C | Fully mix |
| D | Adopt proper container, the preparation that makes like glass scintillation bottle packaging step C |
| E | The packing that step D is obtained seals, and labels in the time of suitably |
In the method for this embodiment, step B has been carried out many-sided observation (before adding the right MPU-295 of component No.2 hydrochloric acid): 1) gel preparation becomes muddy; With 2) with the gel phase ratio that steps A obtains, gel viscosity that step B obtains reduces.In order to solve the muddiness that in 1, occurs, adding triethanolamine and this are effective.In this embodiment, the additional proportion of triethanolamine is that 0.463g triethanolamine (being designated lot number XT0007) adds in the 32.532g gel that step C obtains.
Further describe here and adopt basic placebo cream preparation (base placebo cream formulation) to prepare the right MPU-295 preparation capable of permeating skin of active hydrochloric acid.
Embodiment 2a-placebo O/W emulsifiable paste base formulation (carrier)
Table D2: oil and emulsifiable paste basis (base) preparation (RECRO1-88)
Table D3: the method for preparing of oil and emulsifiable paste base formulation (RECRO1-88)
The right MPU-295 cream preparation of embodiment 2b-transdermal
Table E: right MPU-295 external (topical) the emulsifiable paste 0.5mg/g (RECRO2-1) of hydrochloric acid
Table F: the method for preparing of the right MPU-295 external emulsifiable paste 0.5mg/g of hydrochloric acid (RECRO2-1)
| Step | Describe |
| A | Component No.1 is dispensed in the 100ml glass beaker |
| B | Add component No.2 |
| C | Fully mix |
| D | Adopt proper container, pack the preparation that the C step makes like 20ml glass scintillation bottle |
| E | The packing of sealing step D is labelled in the time of suitably |
Embodiment 3a-placebo O/W emulsifiable paste base formulation (carrier)
Table F1: oil and water and milk cream base plinth (substrate, base) (RECRO1-98)
Table F2: the method for preparing of oil and water and milk cream base plinth (RECRO1-98)
The right MPU-295 cream preparation of embodiment 3b-transdermal
Table G: the composition of the right MPU-295 external cream preparation 0.5mg/g of hydrochloric acid (RECRO2-2)
Table H: the method for preparing of the right MPU-295 external emulsifiable paste 0.5mg/g of hydrochloric acid (RECRO2-2)
| Step | Describe |
| A | Component No.1 is dispensed in the 100ml glass beaker |
| B | Add component No.2 |
| C | Fully mix |
| D | Adopt proper container, pack the preparation that the C step makes like 20ml glass scintillation bottle |
| E | The packing of sealing step D, label suitably the time |
Embodiment 4a-placebo O/W emulsifiable paste base formulation (carrier)
Table H1: oil and water and milk cream base plinth (RECRO1-100)
Table H2: the method for preparing of oil and water and milk cream base plinth (RECRO1-100)
The right MPU-295 cream preparation of embodiment 4b-transdermal
Table I: the right MPU-295 external emulsifiable paste 0.5mg/g (RECRO2-3) of hydrochloric acid
Table J: the method for preparing of the right MPU-295 external emulsifiable paste 0.5mg/g of hydrochloric acid (RECRO2-3)
| Step | Describe |
| A | Component No.1 is dispensed in the 100ml glass beaker |
| B | Add component No.2 |
| C | Fully mix |
| D | Adopt proper container, pack the preparation that the C step makes like 20ml glass scintillation bottle |
| E | The packing of sealing step D, label suitably the time |
Embodiment 5a-placebo O/W silicone base formulation (carrier)
Table J1:RECRO1-86-oil and water silicone emulsion (RECRO1-85)
Table J2:RECRO 1-86-oil and water silicone emulsion (RECRO1-85) method for preparing
The right MPU-295 cream preparation of embodiment 5b-transdermal
Table J3: the right MPU-295 0.5mg/g external silicone emulsion preparation (RECRO 1-85) of hydrochloric acid
| No. | Material | % | g/50g | Lot number |
| 1 | The right MPU-295 of hydrochloric acid | 0.05 | 0.025 | 1224654349 |
| 2 | The silicone emulsion basis, pH 8.5 | 99.95 | 49.975 | Recro1-86 |
| Amount to | 100.000 | 50.000 |
Table J4: the method for the right MPU-295 0.5mg/g external silicone emulsion of hydrochloric acid (RECRO 1-85)
Here several kinds of exemplary formulation give the dog class to confirm the absorption and other performance characteristics as the right MPU-295 delivering compositions of externally applied transdermal.In those compositionss of measuring, the compositions that is identified as Recro 1-85 among this paper provides ideal right MPU-295 system level.These preparations are applicable to the pain and the relevant symptoms of treatment dog class at least, also applicable to comprising other human mammal.The foregoing description only is exemplary, and is not intended to limit scope of the present invention.Several kinds of exemplary externally applied transdermal preparations are tested on animal, and other is being studied and/or is testing comprises ethanol gel, oil, aqueous emulsion frost (water emulsion cream) and other.The correlated results of relevant animal testing is summed up in the text.
The clinical implementation example
1 phase of clinical research (REC-10-006)
Based on relating to the successful experiment of preparation capable of permeating skin in animal, some preparations and administration thereof and Therapeutic Method are carried out and tested and test at human body.The human preparation derives from exemplary zooscopy preparation, but under the condition that meets cGMP requirement and other human supervision requirement, prepare.(1 phase of aka is studied) in the clinical trial in early days, the illustrative embodiments of some externally applied transdermal preparations and method be existing the application in the mankind.The exemplary formulation of in these clinical trials, using so far is following:
People's pain management.From 2000, its standard to pain assessment and processing was revised by joint committee, and in medical treatment and nursing, it is more and more important that pain therapy becomes.Be commonly referred to as " the 5th vital sign (fifth vital sign) ", the experimenter now must be through conventional pain symptom assessment, so that suitably adjust therapeutic scheme.Although increasing attention focuses on the problem of patient's comfort level and quality of life, it is identical that obtainable tools range roughly keeps.Present medicine covers full effect scope, from 1-2h is provided the fugitive medicine of the effect of releiving, reaches the replaceable preparation of 72h to analgesic activity.Simultaneously, these dosage forms rely on a series of similar activity compositions usually, and they play a role through the approach of similar opioid drug usually, so that the effect of releiving (morphine, oxycodone, fentanyl) to be provided.As a result, though general opioid drug does not have the highest limit of effect, the use of high dose and multiple opioid drug may increase the incidence rate of adverse events, so need between symptom and side effect, make a policy.
Right MPU-295 is a kind of optionally α
2-adrenoceptor agonists, its selectivity are about 10 times of clonidine.Right MPU-295 utilizes its calm effect; In acute and clinical setting, have the permanent history that the safe vein injection is used, and be designated trade name
and use.During low dosage, right MPU-295 has been observed to has analgesia and angst resistance effect, and the risk that breathes no more and suppress.
The application of right MPU-295 transdermal dosage form provides a kind of Noninvasive mechanism of prolong drug picked-up.The ingestion of medicines of this prolongation has promoted the prolongation of active duration, has potential advantages for chronic pain patient.Right MPU-295 has the potential of pain management, and does not have extra sedation or respiration inhibition effect.Suitable application can reduce subject discomfort, keeps it to participate in active ability every day simultaneously.
First kind of human use of the exemplary preparation capable of permeating skin described in the literary composition is designed to assess two right MPU-295 preparation capable of permeating skin, is identified as DEX-TD.02 and DEX-TD.03, safety, toleration and pharmacokinetic property.Pharmacokinetics observation will concentrate on assesses that right MPU-295 passes the absorption of application on human skin and by the influence that increases dosage.
The research purposeHuman research's purpose is to estimate single safety, toleration and pharmacokinetic property by the right MPU-295 of the transdermal that increases dosage in healthy male and the female subjects body.
ProjectWhole research design pursues the 1 phase clinical research that increases, intersects at the intravital open-label of health volunteer, single dose, dosage; Its objective is two kinds of right MPU-295 preparation capable of permeating skin of assessment, the safety of DEX-TD.02 and DEX-TD.03, toleration and pharmacokinetic property.Age is the health volunteer in 18-50 year, screens in research station of Australia studying preceding 28 days of medicine.In the screening access process, carry out pharmacohistory, physical examination, infrastest chamber mensuration, 12-helical pitch electrocardiogram (ECG), conceived test, life sign measurement, and signed Informed Consent Form.Before the administration of 1 phase, the research participant is randomized to either (referring to table M) in one of two research treatment sequences.Each participant each according to distribute in the conceptual phase of treating sequence, accept single dose research medicine.The sufficient window phase of administration period interval is so that carry out pharmacokinetic analysis in early stage (about 14 days) to plasma drug level.
Table M: research treatment sequence
Each is interim, and experimenter about 48h (the 3rd day) after the evening before the administration (first day) to the administration receives restriction (confined).Have a bath the morning that the experimenter is asked to before administration, should the zone and after administration, forbid in the 48h having a bath or cleaning.During restricted, the experimenter accepts standard diet every day.Table N provides the medicine in this research, the dosage that applies and external and gives the zone.
Table N: research treatment
Be used for pharmacokinetic analysis from each experimenter at 16 parts of blood samples of each interim collection behind the single dose administration.30,60,90min and 2,3,4,6,8,10,12,18,24,30,36 and 48h these collections are to the time proximity below behind initial dose (0 constantly) and the research drug administration:.Time after medicine being given to the experimenter, give promptly begins.Safety is measured and is comprised AE monitoring, clinical laboratory's mensuration, vital sign detection, physical examination, stimulation assessment and ECG.
The mechanism of research design and matched group.This research evaluation the known drug safety, toleration and the pharmacokinetic property that give through interchangeable route of delivery.Research before inventor and the applicant has shown the safety that right MPU-295 gives through intravenous and Sublingual approach.
Before said like this paper, inventor and applicant's preliminary research has been utilized the preparation DEX-TD in the animal model (dog class and pig) and has been carried out, thereby foundation is provided for normal volunteer's predose.The dosage that uses in this research has been assessed the absorbent properties that DEX-TD.02 and DEX-TD.03 put on application on human skin by increasing the model discriminated union, comprises how it depends on the dosage that is applied and change.The purpose of cross-over design (crossover design) is the relatively absorption of these two kinds of preparations in phase experimenter on the same group.In the experimenter of an inferior group, preparation capable of permeating skin gives to a zone of skin, and covers upward dressing thing (dressing) (" sealing ") apace.The dressing thing that is adopted is TEGADERM
TMBoard dressing thing (TEGADERM
TMBe the registered trade mark of 3M company).In another inferior group experimenter, preparation capable of permeating skin gives to skin, does not cover (" non-sealing ").Based on the dressing administration experience of good formation, the inventor be expected at preparation capable of permeating skin skin apply among the patient who is applied with the dressing thing on the site (abdominal part) absorb more.Yet, it is shocking that apply in the Asia group that does not apply the dressing thing on the site at skin, the absorption of DEX-TD.02 is significantly higher.And the result shows, it is necessary or desirable not sealing, and makes at least the compositions of DEX-TD.02 become real " no paster (patchless) " transdermal (that is, no dressing thing need not comprise the paster of said preparation).Said preparation is stable in the time of on being applied to skin, and need not dressing thing or other coverings and be easy to be absorbed.Because the pharmacokinetics focus of this research is not so need contrast crowd (control population).
After understanding the pharmacokinetics result of 1 phase, decision drug-delivery preparation DEX-TD.02 only in I1 phase clinical research.This part is because the significantly lower absorption of DEX-TD.03.Because this research is to seek high the absorption, so that the systemic absorption of right MPU-295 to be provided, thereby the DEX-TD.02 preparation is more suitable for further clinical experiment in this research.And DEX-TD.03, especially its lower absorption rate and low-down system absorb, and perhaps are more suitable for being used to treat other pain management application, like neuropathic treatment under local skin and/or the dura mater.It should be noted that the handled any experimenter of each preparation in the research of 1 phase, all do not have to observe or the report sedation.
The clinical research of 2 phases
Purpose.The purpose of 2 phases clinical research is the Cpss-time graph after calculating the right MPU-295 dosage of 0.5g in DEX-TD.02 preparation every day 1 time and every day, 2 externals applying; Adopt applicant's single dose by increasing the data (1 phase, (REC-10-006)) that research produces.
Research design.PC-the time data of clinical research #REC-10-006 right-of-center in political views MPU-295 is used for predicting 0.25g, 0.5g and 1g dosage every day 1 time (QD) and Css-time graph that every day, 2 (BID) externals applied.Adopt following three experimenters' data: 1001,1004 and 1005.These three experimenters participated in following treatment part (arm, arms): treatment A (dosage 0.25g), treatment C (dosage 0.5g) and treat E (dosage 1.0g).Clinical research #REC-10-006 has the single dose of a plurality of treatment parts (treatment A, B, C, D and E) by increasing research (single ascending-dose study).(before the administration, pre-dose) obtain after (0 hour) and the administration: 0.5,1,1.5,2,3,4,6,8,10,12,18,24,30,36 and 48h by the following fixed time at initial dose for the plasma sample that is used for pharmaceutical analysis.The lower limit of quantitation of bioanalysis experiment is 0.02ng/mL.It should be noted that in the research of 2 phases any experimenter that arbitrary preparation is treated does not observe or the report sedation.
Methodology and analysis.All pharmacokinetic parameters obtain through regional analysis (compartmental analysis).PC-the time data of 1 phase (REC-10-006) right-of-center in political views MPU-295 is used for predicting the Css-time graph of 0.25g, 0.5g and 1.0g dosage administration every day 1 time (QD) and 2 times (BID).The data that adopt come from three experimenters (identifier 1001,1004 and 1005) that participate in following treatment part: A (dosage 0.25g), C (dosage 0.5g) and E (dosage 1.0g).Pharmaceutical analysis be obtained from before the administration with blood sample and administration after the following fixed time: 0.25,0.5,0.75,1,1.5,2,2.5,3,4,5,6,7,8,12,24,48 and 72h.Most of (67%) PC all is lower than measurable horizontal 0.02ng/mL; Therefore, the more high-grade computer nonlinear mixed-effect model method of PK parameter employing (as, colony's pharmacokinetics [PopPK]) calculate.Nonlinear mixed-effect model utilizes software Monolix3.1 version (institut national de recherche en infomatique et automatique [INRIA]) to carry out.In case calculate the PK parameter and produce single dose concentration, data are inputed to WinNonlin
TM5.2 version (WinNonlin
TMCopyright
2008, Pharsight company), the Cpss-time graph that is obtained by QD and BID administration is carried out the nonparametric stack.
Calculating from the pharmacokinetic parameter of single dose data.As previously mentioned, calculate the PK parameter through the nonlinear mixed-effect model that utilizes Monolix3.1 software.The single chamber linear model (linear one-compartment model) that three experimenters' (1001,1004 and 1005) of treatment below participating in part: A (dosage 0.25g), C (dosage 0.5g) and E (dosage 1.0g) right MPU-295 PC match to zero level absorbs.Provided the concentration of match and observation among Fig. 1.In Fig. 1, note: numeral is that the experimenter identifies (for example, 1001,1004 or 1005); Subscript (for example A, C, E) is treatment: A (dosage 0.25g), C (dosage 0.5g) or E (dosage 1.0g); Plus sige (+) is meant that recording right MPU-295 concentration is higher than dose limit; And asterisk (*) is meant that right MPU-295 concentration is lower than dose limit (0.02ng/mL); And solid line constitutes the PK curve of best fit.The inspection match shows with observation concentration-time curve (Fig. 1), and the single chamber (solid line) that zero level absorbs has appropriately been described concentration that can quantitative right MPU-295 (plus sige) and consistent with the sample that is considered to be lower than measurable level (BQL) (asterisk).
Generally speaking, as shown in Figure 2, the model of experimenter's administration and observation have good concordance.Fig. 2 shows; Value (coming self model) and the observation of prediction have concordance closely, and as through what scattering showed, it approaches the Molded Line of observation; This Molded Line is equal to predictive value, and shows that most of BQL value is along with the value of coming self model keeps constant.For Fig. 2, note: rhombus refers to measure concentration and is higher than measurable limit value; Asterisk refers to measure concentration and is lower than metering limit value (0.02ng/mL); Straight line refers to observe the single line (line of unity) of concentration=prediction concentrations; Curve is the Trendline (trend line) of tracing point.
Pharmacokinetic parameter by match derives is seen table P1.As if right MPU-295 epidermis applies and can absorb with constant rate of speed in the time at about 20h, and the half-life is about 15h.Accumulative total about 2.2x of the factor and 1.5x calculate to BID and QD administration respectively.
The pharmacokinetic parameter that table P1.1 phase clinical research (REC-10-06) is measured
* V/F: volume of distribution is divided by the drug absorption mark
k
El: apparent first (first-order) elimination rate constant of crossing
The calculating of the Css of BID and QD administration.As previously mentioned, when calculating the PK parameter and producing single dose concentration, data are inputed to WinNonlin
TM5.2 version (WinNonlin
TMCopyright
2008, Pharsight company).Adopt the Cpss-time graph of nonparametric stack prediction QD and BID administration.Each dosage of nonparametric stack supposition medicine is independent of every kind of other dosage and plays a role, and the speed of the absorption of each dosing interval and average whole body removing is identical with degree.Linear pharmacokinetics is applicable to that the DM that makes in many metered scheme can be adjusted.
In order to predict the drug level from multiple dose administration, characterizing fully of concentration-time curve is necessary behind the single dose administration.This means, must know enough time point t
i(i=1,2 ..., n), characterize drug absorption and elimination process.Need two hypothesis: the independence of each dosage effect and the linearity of potential pharmacokinetics to data.The former supposes that the effect of each dosage can be independent of the influence of other dosage.The latter, linear pharmacokinetics supposes that the variation meeting of drug level is linear change with dosage.
0.25g the prediction PC-time graph of (tx A), 0.5g (tx C) and 1.0g (tx E) stable state that is administered once every day is as shown in Figure 3.Predict steady-state PC-the time graph that is administered twice every day is as shown in Figure 4.To two kinds of dosage regimens (QD and BID), the PC-time graph during the gained stable state is quite smooth.This is owing to prolongation zero level (zero-order) diffusion and the long half-life of medicine from skin corium to systemic circulation.The predict steady-state PC of BID and QD provides among the R3 with showing at table Q2 respectively.
The Cpss (ng/mL) of table twice administration Q2. every day
The Cpss (ng/mL) of table R3. administration once a day
2 phase result and conclusions.Fig. 3 and Fig. 4 provided based on once a day with every day twice dosage regimen use the clinical research of DEX-TD.02, in time predict steady-state PC in the human body of growing up.Recall the right MPU-295 concentration range of target stable state that in this research, is used as analgesics and does not have a sedation and be 0.1 to 0.2ng/mL.Therefore, Fig. 3 and Fig. 4 are clear to be shown, this BID administration that can pass through 0.5g dosage (this is with the lower limit of reach) or 1.0g dosage (this is with the upper limit of reach) realizes.In this embodiment, the Css generation multiple dosing the 4th day that needs of forecasting institute or after.Based on this model, being administered once every day is still a kind of challenge, because DEX-TD.02 preparation and DEX-TD.03 preparation are administered once every day, no matter dosage is 0.5g or 1g, all can not make Cpss reach target zone (0.1 to 0.2ng/mL) fast.Again, adopt DEX-TD.02 or similar formulations, will just can reach Cpss through behind 4 days the multiple dose administration at least.Yet; Knowledge and information according to the inventor among desired and this paper; No matter be at short notice or through alternative dosage regimen, these can show Transdermal absorption with other external preparation, and in mammal, reach the target Cpss of required right MPU-295.For example; Administration reaches that the stable state that needs can be used the Sublingual of fast Absorption, the transdermal composition that passes through mucosa and/or fast Absorption (for example; The solvent carrier such as compatible carrier and the preparation of DMSO, ethanol and other pharmacy that comprise fast Absorption), realize in conjunction with the combination of the right MPU-295 preparation capable of permeating skin of lasting, controlled, the release of describing in the literary composition that prolongs and absorption.
These descriptions are reference example property embodiments and making, and to those skilled in the art, under the prerequisite that does not depart from the scope of the invention, can carry out various changes for its key element, and replaceable equivalent.And, in order to adapt to the demand of special circumstances or material, under the prerequisite that does not depart from elemental range of the present invention, also can make multiple adjustment.Specific term in addition, in description of the present invention, disclosed illustrative embodiments, although possibly be used; But except as otherwise noted; They only use with general and descriptive implication, be not used in the purpose of restriction, so the scope of claims are not limited yet.And those skilled in the art will understand, the rank order that some step described herein and method can be other, and perhaps some step can merge.Therefore, accompanying claims is not intended to be restricted to the specific implementations that this paper discloses.
Claims (25)
1. the treatment or the method for prevent irritation comprise:
Apply compositions to mammalian skin, said compositions comprises the right MPU-295 in pharmaceutical acceptable carrier or the acceptable salt of its pharmacy or the prodrug of a dosage,
Wherein, said right MPU-295 or the acceptable salt of its pharmacy or prodrug pass through skin absorbs, and produce analgesic activity and do not have sedation.
2. method according to claim 1, wherein, the said dosage of right MPU-295 or the acceptable salt of its pharmacy is extremely about 15mcg/kg of about 0.05 μ g/kg, and wherein, said mammal is behaved.
3. method according to claim 2, wherein, said mammal is behaved, and the transdermal dosage compositions of right MPU-295 or the acceptable salt of its pharmacy is that about 100 μ g are to about 1500 μ g.
4. method according to claim 3 wherein, applies through transdermal and to absorb and get into after said people's the systemic circulation system plasma C of right MPU-295
MaxLess than about 0.30ng/mL.
5. method according to claim 2, wherein, the said step that applies comprises said pharmaceutical composition external is put at least a skin in following: shank, arm, abdominal part, chest, groin, cervical region, back and shoulder.
6. method according to claim 5, wherein, the said step that applies comprises that ointment, lotion or gel with said pharmaceutical composition are applied on the said mammiferous said skin.
7. method according to claim 6, wherein, the said step that applies does not require with the dressing thing to cover said skin after giving said pharmaceutical composition to said mammalian skin.
8. method according to claim 2, wherein, in after applying said pharmaceutical composition, be right after at least 6 hours, people's static mean arterial blood pressure changes and is not more than about 20mmHg.
9. method according to claim 2, wherein, in after applying said pharmaceutical composition, be right after at least 6 hours, it is clear-headed that said people can keep, and can response instruction, and said people be vigilance with orientation.
10. method according to claim 1, wherein, said right MPU-295 or the acceptable salt of its pharmacy and one or more other analgesics give jointly.
11. method according to claim 10, wherein, said pharmaceutical composition is given off and on and is treated the sudden pain that said one or more other analgesics can not fully be controlled.
12. method according to claim 2, wherein, said pain is constitutional pain.
13. method according to claim 12, wherein, said constitutional pain is selected from by neuralgia, myalgia, hyperpathia, hyperpathia, neuritis and group that neuropathy constituted.
14. method according to claim 2, wherein, said pain is relevant with cancer, viral infection, physical trauma, arthritis, headache or back pain, or is caused by cancer, viral infection, physical trauma, arthritis, headache or back pain.
15. method according to claim 14, wherein, said physical trauma and surgical operation, burn or blunt made every effort to achieve and hindered relevantly, or caused by surgical operation, burn or the blunt wound of making every effort to achieve.
16. the treatment or the method for prevent irritation comprise:
Pharmaceutical composition is applied on the mammalian skin film, and said pharmaceutical composition is included in right MPU-295 or acceptable salt of its pharmacy or the prodrug in the pharmaceutical acceptable carrier,
Wherein, said right MPU-295 or the acceptable salt of its pharmacy or prodrug be through said skin absorbs, and produce analgesic activity and do not have sedation.
17. the treatment or the method for prevent irritation comprise:
Effectively treat in mammal the back or the amount of prevent irritation to give, and the pharmaceutical composition that will comprise the systemic absorption of right MPU-295 or acceptable salt of its pharmacy or prodrug gives to said mammalian skin,
Wherein, said pharmaceutical composition provides in right MPU-295 to the said mammiferous systemic circulation system of physiologically active amount with in the speed that gives to produce analgesic effect at least in 6 hours and do not have sedation.
18. analgesic composition; Be included in right MPU-295 or acceptable salt of its pharmacy or prodrug in the pharmaceutically acceptable carrier, said pharmaceutical composition is prepared and adjustment is used for that external gives said mammal through said analgesic composition is applied to mammalian skin.
19. analgesic composition according to claim 18, wherein, said analgesic composition is prepared and adjustment is used for through external gives more than once being applied to said skin every day with said compositions.
20. analgesic composition according to claim 18; Wherein, said analgesic composition is prepared and is adjusted and is used for through said compositions being put on the said at least a skin below mammiferous and external gives: shank, arm, abdominal part, chest, groin, cervical region, back and shoulder.
21. analgesic composition according to claim 18, wherein, the acceptable salt of the pharmacy of said right MPU-295 is the right MPU-295 of hydrochloric acid, and wherein, and said carrier is selected from least a in ointment, gel and the suspending agent.
22. analgesic composition according to claim 21, wherein, said compositions does not require sealing or covers after giving to the mammalian skin.
23. analgesic composition according to claim 18, wherein, said analgesic composition is packaged in the allotter.
24. one kind is used to treat or the device of prevent irritation, said device comprises:
Analgesic composition is included in right MPU-295 or acceptable salt of its pharmacy or prodrug in the pharmaceutically acceptable carrier, and
Allotter, it holds and distributes said analgesic composition.
25. device according to claim 24, wherein, said device comprises and applies device, saidly applies that device is designed and arrangement is used for said compositions is delivered to mammalian skin from said device.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29344010P | 2010-01-08 | 2010-01-08 | |
| US61/293,440 | 2010-01-08 | ||
| PCT/US2011/020462 WO2011085162A2 (en) | 2010-01-08 | 2011-01-07 | Topical transdermal dexmedetomidine compositions and methods of use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102753169A true CN102753169A (en) | 2012-10-24 |
Family
ID=44306157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800088869A Pending CN102753169A (en) | 2010-01-08 | 2011-01-07 | Topical transdermal dexmedetomidine compositions and methods of use thereof |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20130072532A1 (en) |
| EP (1) | EP2521544A4 (en) |
| JP (1) | JP2013516482A (en) |
| CN (1) | CN102753169A (en) |
| AU (1) | AU2011204315A1 (en) |
| CA (1) | CA2786598A1 (en) |
| MX (1) | MX2012007933A (en) |
| NZ (2) | NZ703808A (en) |
| RU (1) | RU2012133969A (en) |
| WO (1) | WO2011085162A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105764496A (en) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
| CN105764495A (en) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | Methods and compositions for managing pain comprising dexmedetomidine transdermal compositions |
| CN107929234A (en) * | 2017-12-25 | 2018-04-20 | 温州医科大学附属第医院 | A kind of new external preparation lotion applied to burn wound reparation |
| CN113577556A (en) * | 2021-08-01 | 2021-11-02 | 武汉左点科技有限公司 | Biofeedback electrical stimulation method and device for vagina rehabilitation |
| WO2024037545A1 (en) * | 2022-08-17 | 2024-02-22 | 宜昌人福药业有限责任公司 | Dexmedetomidine transdermal composition, transdermal patch, and method for preparing transdermal patch and use thereof |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG11201403094TA (en) * | 2011-12-11 | 2014-10-30 | Recro Pharma Inc | Intranasal dexmedetomidine compositions and methods of use thereof |
| US20140329874A1 (en) * | 2013-05-06 | 2014-11-06 | Allergan, Inc. | Alpha adrenergic agonists for the treatment of tissue trauma |
| TWI704933B (en) * | 2013-10-07 | 2020-09-21 | 美商帝國製藥美國股份有限公司 | Dexmedetomidine transdermal delivery devices and methods for using the same |
| FI3054934T3 (en) * | 2013-10-07 | 2024-07-19 | Teikoku Pharma Usa Inc | Methods and compositions for treating withdrawal syndromes using non-sedative dexmedetomidine transdermal compositions |
| KR101831290B1 (en) | 2013-10-07 | 2018-02-22 | 테이코쿠 팔마 유에스에이, 인코포레이티드 | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
| MA41689A (en) * | 2014-10-15 | 2017-08-22 | Bioxcel Corp | PREVENTION OR TREATMENT OF SLEEP DISORDERS WITH A DEXMEDETOMIDINE FORMULATION |
| KR20190060007A (en) * | 2016-10-31 | 2019-05-31 | 테이코쿠 팔마 유에스에이, 인코포레이티드 | How to manage pain using Dexmedetomidine transdermal device |
| EP4371554A3 (en) | 2016-12-31 | 2024-08-07 | BioXcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| SG11202012772XA (en) | 2018-06-27 | 2021-01-28 | Bioxcel Therapeutics Inc | Film formulations containing dexmedetomidine and methods of producing them |
| US20220211672A1 (en) | 2019-05-01 | 2022-07-07 | Clexio Biosciences Ltd. | Methods of treating pruritus |
| US11185532B2 (en) | 2019-05-01 | 2021-11-30 | Clexio Biosciences Ltd. | Methods of treating pruritus |
| WO2021016112A2 (en) | 2019-07-19 | 2021-01-28 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| US11806334B1 (en) | 2023-01-12 | 2023-11-07 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049450A (en) * | 1989-08-18 | 1991-02-27 | 天鹅探究有限公司 | Method and apparatus that dexmedetomidine uses through skin |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5217718A (en) * | 1989-08-18 | 1993-06-08 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
| FI894911A0 (en) * | 1989-10-17 | 1989-10-17 | Farmos Oy | EN TERAPEUTISKT VAERDEFULL FOERENING. |
| GB9111732D0 (en) * | 1991-05-31 | 1991-07-24 | Orion Yhtymae Oy | The use of certain salts of medetomidine and its optically active enantiomers to regulate the rate of transdermal administration of the drugs |
| GB9913677D0 (en) * | 1999-06-11 | 1999-08-11 | Imperial College | Formulation |
| AUPR184500A0 (en) * | 2000-12-01 | 2001-01-04 | Drug Delivery Solutions Pty Ltd | Dispensing device |
| WO2002089794A1 (en) * | 2001-05-07 | 2002-11-14 | Universite Catholique De Louvain | Method for treating neuropathic pain and pharmaceutical preparation therefor |
| IL147921A0 (en) * | 2002-01-31 | 2002-08-14 | Abdulrazik Mohammad | A method for treating central nervous system disorders by ocular dosing |
| US20050058696A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
| GB0611241D0 (en) * | 2006-06-07 | 2006-07-19 | Daniolabs Ltd | The treatment of increased sebum production |
-
2011
- 2011-01-07 NZ NZ703808A patent/NZ703808A/en not_active IP Right Cessation
- 2011-01-07 NZ NZ601195A patent/NZ601195A/en not_active IP Right Cessation
- 2011-01-07 JP JP2012548137A patent/JP2013516482A/en active Pending
- 2011-01-07 MX MX2012007933A patent/MX2012007933A/en not_active Application Discontinuation
- 2011-01-07 WO PCT/US2011/020462 patent/WO2011085162A2/en active Application Filing
- 2011-01-07 RU RU2012133969/15A patent/RU2012133969A/en not_active Application Discontinuation
- 2011-01-07 CA CA2786598A patent/CA2786598A1/en not_active Abandoned
- 2011-01-07 US US13/520,959 patent/US20130072532A1/en not_active Abandoned
- 2011-01-07 EP EP11732180.2A patent/EP2521544A4/en not_active Withdrawn
- 2011-01-07 CN CN2011800088869A patent/CN102753169A/en active Pending
- 2011-01-07 AU AU2011204315A patent/AU2011204315A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049450A (en) * | 1989-08-18 | 1991-02-27 | 天鹅探究有限公司 | Method and apparatus that dexmedetomidine uses through skin |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105764496A (en) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
| CN105764495A (en) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | Methods and compositions for managing pain comprising dexmedetomidine transdermal compositions |
| CN110604728A (en) * | 2013-10-07 | 2019-12-24 | 帝国制药美国公司 | Methods and compositions comprising dexmedetomidine transdermal compositions for managing pain |
| CN107929234A (en) * | 2017-12-25 | 2018-04-20 | 温州医科大学附属第医院 | A kind of new external preparation lotion applied to burn wound reparation |
| CN107929234B (en) * | 2017-12-25 | 2021-07-23 | 温州医科大学附属第一医院 | External preparation paste applied to burn wound repair |
| CN113577556A (en) * | 2021-08-01 | 2021-11-02 | 武汉左点科技有限公司 | Biofeedback electrical stimulation method and device for vagina rehabilitation |
| WO2024037545A1 (en) * | 2022-08-17 | 2024-02-22 | 宜昌人福药业有限责任公司 | Dexmedetomidine transdermal composition, transdermal patch, and method for preparing transdermal patch and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2012133969A (en) | 2014-02-20 |
| JP2013516482A (en) | 2013-05-13 |
| US20130072532A1 (en) | 2013-03-21 |
| NZ601195A (en) | 2015-02-27 |
| AU2011204315A1 (en) | 2012-08-02 |
| MX2012007933A (en) | 2012-08-15 |
| WO2011085162A2 (en) | 2011-07-14 |
| EP2521544A2 (en) | 2012-11-14 |
| CA2786598A1 (en) | 2011-07-14 |
| NZ703808A (en) | 2016-01-29 |
| WO2011085162A3 (en) | 2011-11-17 |
| EP2521544A4 (en) | 2013-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102753169A (en) | Topical transdermal dexmedetomidine compositions and methods of use thereof | |
| Khan et al. | Challenges and innovations of drug delivery in older age | |
| JP6505177B2 (en) | Intranasal dexmedetomidine compositions and methods of use thereof | |
| JP6172938B2 (en) | Sublingual composition of dexmedetomidine and method of use thereof | |
| US20090042940A1 (en) | Methods and compositions using cholinesterase inhibitors | |
| TW200904407A (en) | Oronasopharyngeally deliverable pharmaceutical composition for the prevention/alleviation and/or treatment of restless limb disorder | |
| JP6511492B2 (en) | Treatment of symptoms related to female gastroparesis | |
| CN109453169B (en) | Application of bulleyaconitine A | |
| EP4218750A1 (en) | The use of melanin in therapy of subjects with trisomy 21 | |
| Rataboli | Clinical Pharmacology and Rational Therapeutics | |
| NZ626999B2 (en) | Intranasal dexmedetomidine compositions and methods of use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20121024 |